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Hepatocellular carcinoma (HCC) is a malignancy with one of the worst prognoses. Long noncoding RNAs (lncRNAs) may be important in cancer development and may serve as new biomarkers for the diagnosis and treatment of various tumors, according to mounting research. The purpose of this study was to investigate the expression of INKA2-AS1 and clinical importance in HCC patients. The TCGA database was used to obtain the human tumor samples, while the TCGA and GTEx databases were used to gather the human normal samples. We screened differentially expressed genes (DEGs) between HCC and nontumor tissues. Investigations were made into the statistical significance and clinical significance of INKA2-AS1 expression. A single-sample gene set enrichment analysis (ssGSEA) was used to examine potential relationships between immune cell infiltration and INKA2-AS1 expression. In this investigation, we found that HCC specimens had considerably greater levels of INKA2-AS1 expression than nontumor specimens. When utilizing the TCGA datasets and the GTEx database, high INKA2-AS1 expression showed an AUC value for HCC of 0.817 (95% confidence interval: 0.779 to 0.855). Pan-cancer assays revealed that numerous tumor types had dysregulated levels of INKA2-AS1. Gender, histologic grade, and pathologic stage were all substantially correlated with high INKA2-AS1 expression. A survival study indicated that HCC patients with high INKA2-AS1 expression have shorter OS, DSS, and PFI than those with low INKA2-AS1 expression. Multivariate analysis indicated that INKA2-AS1 expression was an independent prognostic factor for OS of patients with HCC. According to immune analysis, the expression of INKA2-AS1 was favorably correlated with T helper cells, Th2 cells, macrophages, TFH, and NK CD56bright cells and negatively correlated with Th17 cells, pDC, cytotoxic cells, DC, Treg, Tgd, and Tcm. The results of this study collectively suggest that INKA2-AS1 has the potential to be a novel biomarker for predicting the prognosis of HCC patients as well as a significant immune response regulator in HCC.

Surface micro-morphology of 304 SS before corrosion (a), after corrosion in molten NaNO3–NaCl–NaF salt (b) and molten NaNO3–NaCl–NaF vapor (c). (Local enlarged region of A1 (b-1), A2 (c-1) and A3 (c-2)).

Liposomal drug delivery for cancer therapy can be limited due to drug leakage in circulation. Here, we develop a new method to enhance the stability of actively loaded liposomal doxorubicin (DOX) through embedding a stiff nanobowl in the liposomal water cavity. Nanobowl-supported liposomal DOX (DOX@NbLipo) resists the influence of plasma protein and blood flow shear force to prevent drug leakage. This approach yields improved drug delivery to tumor sites and enhanced antitumor efficacy. Compared to alternative methods of modifying liposome surface and composition for stability, this approach designs a physical support for an all-aqueous nanoliposomal cavity. Nanobowl stabilization of liposomes is a simple and effective method to improve carrier stability and drug delivery.

Long-term survivals of patients with hepatocellular carcinoma (HCC) remain unfavorable, which is largely attributed to active carcinogenesis. Growing studies have suggested that the reliable gene signature could act as an independent prognosis factor for HCC patients. We tried to screen the survival-related genes and develop a prognostic prediction model for HCC patients based on the expression profiles of the critical survival-related genes. In this study, we analyzed TCGA datasets and identified 280 genes with differential expressions (125 increased genes and 155 reduced genes). We analyzed the prognosis value of the top 10 dysregulated genes in HCC patients and identified three critical genes, including FCN3, CDC20, and E2F1, which were confirmed to be associated with long-term survival in both TCGA and ICGC datasets. The results of the LASSO model screened CDC20 and FCN3 for the development of the prognostic model. The CDC20 expression was distinctly increased in HCC specimens, while the FCN3 expression was distinctly decreased in HCC. At a suitable cutoff, patients were divided into low-risk and high-risk groups. Survival assays revealed that patients in high-risk groups exhibited a shorter overall survival than those in low-risk groups. Finally, we examine the relationships between risk score and immune infiltration abundance in HCC and observed that risk score was positively correlated with infiltration degree of B cells, T cell CD4+ cells, neutrophil, macrophage, and myeloid dendritic cells. Overall, we identified three critical survival-related genes and used CDC20 and FCN3 to develop a novel model for predicting outcomes and immune landscapes for patients with HCC. The above three genes also have a high potential for targeted cancer therapy of patients with HCC.

In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity, is developed. The liposomal membrane is doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggers the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also myeloid-derived suppressor cell (MDSC) inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes is more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicates therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment.

Corrosion behavior of 304 stainless steel in molten NaNO

Domestic wastewater depth processing and reclamation are essential in the alleviation of global water shortage. In this study, an innovative filter media (i.e., Fe3O4@Carbon filter media [FCM]) was...

Clay minerals, as abundant natural resources, are among the most suitable supporting materials for nano metal. In this manuscript, new Fe 3 O 4 nanoparticle/rectorite (Fe 3 O 4 /rectorite) catalysts are developed via in-situ precipitation oxidation reaction. Various physicochemical characterizations of Fe 3 O 4 /rectorite show that Fe 3 O 4 nanoparticles (nano-Fe 3 O 4 ) with an average particle diameter of approximately 10–20 nm are effectively loaded on the surface of acid leached rectorite (Al-rectorite) and have low coaggregation and improved dispersion. Moreover, the catalytic activity of Fe 3 O 4 /rectorite on degradation of P-chlorophenol by heterogeneous Fenton method is studied. Results of degradation experiments show that Fe 3 O 4 /rectorite has higher degradation efficiency of P-chlorophenol than bare nano-Fe 3 O 4 . Regeneration studies also show that Fe 3 O 4 /rectorite maintains 100% of its maximum P-chlorophenol degradation capacity after seven consecutive cycles. Fe 3 O 4 /rectorite can be easily separated by magnetic separation, and thus has good stability and reusability. The degradation mechanism of Fe 3 O 4 /rectorite is adsorption coupled with a Fenton-like reaction, which accounts for P-chlorophenol degradation of up to 625 mg/g. This work demonstrates a new composite material for the effective remediation of refractory organic compounds from wastewater.

In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1β, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.

Highlights Small-sized trastuzumab-targeted micelles (T-MP) were engineered using a surfactant-stripping approach that yielded concentrated phthalocyanines with strong near infrared absorption.T-MP accumulated more in the lymph node (LN) metastases of orthotopic colorectal cancer compared to the micelles conjugated with control IgG.Following surgical resection of the primary tumor, minimally invasive photothermal treatment of the metastatic LN with T-MP, but not the control micelles, extended mouse survival. Tumor lymph node (LN) metastasis seriously affects the treatment prognosis. Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration. Here, we speculate through introducing targeting capacity, the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy. Trastuzumab-targeted micelles (

BackgroundTuberculosis (TB) is a leading cause of morbidity and mortality in underdeveloped and developing countries. Disseminated TB may induce uncommon and potentially fatal secondary hemophagocytic lymphohistiocytosis (HLH). Timely treatment with anti-tuberculosis therapy (ATT) and downmodulation of the immune response is critical. However, corticosteroid treatment for TB-associated HLH remains controversial. Herein, we report a successful case of disseminated TB-associated HLH in a pregnant woman with Evans syndrome accompanied by a literature review.Case PresentationA 26-year-old pregnant woman with Evans syndrome was transferred to the Third Affiliated Hospital of Sun Yat-Sen University because of severe pneumonia. She presented with cough, fever, and aggravated dyspnea. Nested polymerase chain reaction for Mycobacterium tuberculosis (M. tuberculosis) complex in sputum was positive. Sputum smear sample for acid-fast bacilli was also positive. Metagenome next-generation sequencing (mNGS) of the bronchoalveolar lavage fluid identified 926 DNA sequence reads and 195 RNA sequence reads corresponding to M. tuberculosis complex, respectively. mNGS of blood identified 48 DNA sequence reads corresponding to M. tuberculosis. There was no sequence read corresponding to other potential pathogens. She was initially administered standard ATT together with a low dose of methylprednisolone (40 mg/day). However, her condition deteriorated rapidly with high fever, acute respiratory distress syndrome, pancytopenia, and hyperferritinemia. Bone marrow smears showed hemophagocytosis. And caseating tuberculous granulomas were found in the placenta. A diagnosis of disseminated TB-associated HLH was made. Along with the continuation of four drug ATT regimen, therapy with a higher dose of methylprednisolone (160 mg/day) combined with immunoglobulin and plasma exchange was managed. The patient’s condition improved, and she was discharged on day 19. Her condition was good at follow-up with the continuation of the ATT.ConclusionsClinicians encountering patients with suspected TB accompanied by unexplainable inflammation not responding to ATT should consider complications with HLH. Timely administration of ATT combined with corticosteroids may result in a favorable outcome.

Hepatocellular carcinoma (HCC) is a malignant tumor and is associated with necroinflammation driven by various immune cells, such as dendritic cells, macrophages and natural killer cells. Innate immune cells can directly affect HCC or regulate the T-cell responses that mediate HCC. In addition, innate immune cells and T cells are not isolated, which means the interaction between them is important in the HCC microenvironment. Considering the current unsatisfactory efficacy of immunotherapy in patients with HCC, understanding the relationship between innate immune cells and T cells is necessary. In the present review the roles and clinical value of innate immune cells that have been widely reported to be involved in HCC, including dendritic cells, macrophages (including kupffer cells), neutrophils, eosinophils, basophils and innate lymphoid cells and the crosstalk between the innate and adaptive immune responses in the antitumor process have been discussed. The present review will facilitate researchers in understanding the importance of innate immune cells in HCC and lead to innovative immunotherapy approaches for the treatment of HCC.

Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano‐Pt) as a catalase‐like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano‐Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano‐Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed “nano‐Pt/VP@MLipo,” is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the VP‐mediated PDT, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano‐Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity., The biomimetic liposomal nano‐Pt (nano‐Pt/VP@MLipo) targets the tumor sites, where oxygen produced by nano‐Pt catalyzation enhances the verteporfin (VP)‐mediated photodynamic therapy (PDT). PDT in turn permeabilizes the liposome membrane for efficient nano‐Pt release. These ultrasmall particles (3–5 nm) achieve penetration in deeper tumor tissue, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy.

OBJECTIVE: To investigate the role of endoplasmic reticulum (ER)-stress of Kupffer cells (KCs) and KCs-derived tumor necrosis factor-α (TNF-α) in medicating apoptosis of hepatic stellate cell (HSC). METHODS: Sixty male SD rats were randomized into control group, model group, ER- stress group, depletion group and KCs block group (n=15). The 4 groups of rats were given intraperitoneal injections (twice a week for 8 weeks) of normal saline (2 mg/kg); 40% CCl4 solution (in peanut oil, 2 mg/kg); 40% CCl4 solution (2 mg/kg) and tunicamycin (1 mg/kg); and 40% CCl4 solution (2 mg/kg) and tunicamycin (1 mg/kg) followed by clodronate liposomes (50 mg/kg), respectively. After the treatments, samples of the liver tissue and serum were collected from the rats from the 4 groups to isolate KC cells, which were co-cultured with LX2 cells. In the depletion group, the rats were injected with anti-rat TNFR mAb (0.35 mg/kg) via the portal vein before isolating the KCs. Liver function examination, Eirius red staining, ELISA, immuno- histochemical staining, and RT-PCR were performed to assess the liver function, liver fibrosis, KC phenotypes, expression of the in fl ammatory factors, and the number of active HSC was detected. The isolated KCs were treated with tunicamycin before co-culture with LX2 cells, and ELISA, RT-PCR and Western blot were performed to examine KC phenotypes, in fl ammatory factors, LX2 cell apoptosis and TNFR/caspase8 pathway activity. RESULTS: Compared with the rats in the control group, the rats in the model group had significantly increased ALT and AST levels, Sirius red staining-positive area, and Desmin-positive cells (activated HSCs) (P < 0.05) with significantly lowered number of CD16-positive KCs (M1), and TNF-α protein and mRNA expression (P < 0.05). Compared with those in the model group, the rats in ER-stress group showed significantly decreased ALT and AST levels, Sirius red staining positivity and Desmin-positive cells (P < 0.05) and increased number of CD16-positive KCs and TNF-α expressions (P < 0.05). In the depletion group, compared with the ER-stress group, the rats had significantly increased ALT and AST levels of, Sirius red staining positivity and Desmin-positive cells (P < 0.05) and reduced CD16- positive KCs and TNF-αexpressions (P < 0.05). In the cell co-culture experiment, the model group showed significantly reduced TUNEL-positive LX2 cells, CD16-positive cells, and expressions of TNFR1, cleaved caspase- 8 and cleaved caspase- 3 in the KCs (P < 0.05) with increased Desmin-positive LX2 cells (P < 0.05). Compared with the model group, the ER- stress group exhibited significantly increased TUNEL-positive LX2 cells, CD16-positive cells and expressions of TNFR, cleaved caspase-8 and cleaved caspase-3 in the KCs (P < 0.05) and decreased Desmin-positive LX2 cells (P < 0.05). In the depletion group, blocking TNFR resulted in significantly decreased expressions of cleaved caspase-8 and cleaved caspase-3 compared with those in ER- stress group (P < 0.05) although there was no significant changed in TNFR expression. CONCLUSION: ER stress of KCs promotes the transformation of KCs towards M1 phenotype and increases the expression of TNF-α, which triggers the apoptosis of HSCs through the TNFR/caspase-8 pathway.

Recent research has revealed the use of graphene oxide (GO) and its derivatives as a potential biomaterial because of their attractive physicochemical characteristics and functional properties. However, if GO and related derivatives are to become useful materials for biomedical applications, it will be necessary to evaluate their biodistribution for health and safety considerations. To obtain a more accurate biodistribution for GO, we (i) developed a postadministration labeling strategy employing DNA-conjugated gold nanoparticles (DNA-AuNPs) to selectively label administered GO in Solvable-treated tissue samples and (ii) constructed an automatic sample pretreatment scheme (using a C18-packed minicolumn) to effectively separate the DNA-AuNP-labeled GO from the unbound DNA-AuNPs and the dissolved tissue matrices, thereby enabling ultrasensitive, interference-free quantification of GO through measurement (inductively coupled plasma mass spectrometry) of the Au signal intensities. The DNA-AuNPs can bind to GO in a concentration- and time-dependent manner. After optimizing the labeling conditions (DNA length, incubation pH, DNA-AuNP concentration, and incubation time) and the separation scheme (sample loading flow rate, rinsing volume, and eluent composition), we found that A20R20-AuNPs (R20: random DNA sequence including A, T, C, and G) had the strongest binding affinity for labeling of the administered GO (dissociation constant: 36.0 fM) and that the method's detection limit reached 9.3 ag L-1 with a calibration curve having a working range from 10-1 to 1010 fg L-1. Moreover, this approach revealed that the intravenously administered GO accumulated predominantly in the liver and spleen at 1 and 12 h post administration, with apparent discrepancies in the concentrations measured using pre- and postadministration labeling strategies.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

A double-diffraction grating interferometer for precision displacement and rotation angle measurement is proposed. The grating interferometer uses electro-optical modulation technology to generate heterodyne light sources, then the "double-diffraction" optical path is established by the cooperation of the mirror and the grating, so that the diffracted light passes through the grating again to generate a diffraction, thereby introducing a doubled phase change to improve the system resolution of the measurement effectively. Then we can obtain the measurement result of the in-plane displacement and the in-plane rotation angle by the measurement result of the light detection. Under this optical path system, the interferometer system can continue to provide correct in-plane displacement and rotation angle measurement information as the grating moves out of plane. The experimental results show that the double-diffraction grating interferometer measurement technology can provide measurement information of double-degree-of-freedom displacement and rotation angle without changing the optical structure. The resolution of the displacement and rotation angle can reach 2 nm and 300 nrad respectively, the repeatability is better than 2 nm and 100 nrad respectively, and the measurement speed limit can reach 160 μm/s, which has excellent measurement performance.

// Ting Jin 1, 2, * , Qun Zhang 3, * , Feng Jiang 1, 2 , Wei-Feng Qin 1, 2 , Qi-Feng Jin 1, 2 , Cai-Neng Cao 1, 2 , Yong-Feng Piao 1, 2 , Xing-Lai Feng 1, 2 , Wei Luo 4 and Xiao-Zhong Chen 1, 2 1 Key Laboratory of Radiation Oncology in Zhejiang Province, Hangzhou, Zhejiang 310022, People’s Republic of China 2 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People’s Republic of China 3 Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510060, People’s Republic of China 4 Department of Radiation Oncology, Sun Yat-Sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, Guangdong 510060, People’s Republic of China * These authors contributed equally to this work Correspondence to: Xiao-Zhong Chen, email: chenxiaozhongfy@163.com Wei Luo, email: luowei2@mail.sysu.edu.cn Keywords: nasopharyngeal carcinoma, neoadjuvant chemotherapy, concurrent chemoradiation, cisplatin, docetaxel Received: March 04, 2017 Accepted: July 12, 2017 Published: October 20, 2017 ABSTRACT Objective: Compare high- vs. low-dose TPF neoadjuvant chemotherapy with chemoradiotherapy in Chinese patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Materials and Methods: Retrospective analysis of 210 stage III/IV NPC patients treated between April 1, 2012 and April 1, 2014; 138 received three cycles of high-dose TPF (H-TPF) every 3 weeks at Zhejiang Cancer Hospital and 72, three cycles of low-dose TPF (L-TPF) every 3 weeks at Sun Yat-Sen University Cancer Center. H-TPF was docetaxel (75 mg/m 2 ; 1 h infusion), cisplatin (75 mg/m 2 ; 0.5–3 h), then 5-fluorouracil (600 mg/m2/day; 4 days). L-TPF was docetaxel (60 mg/m 2 ), cisplatin (65 mg/m 2 ), then 5-fluorouracil (550 mg/m 2 /day; 5 days). All patients received chemoradiotherapy. Results: During neoadjuvant chemotherapy, treatment delays were more frequent for H-TPF than L-TPF (33.3% vs. 19.4%; P = 0.034). During chemoradiotherapy, grade III–IV anemia, thrombocytopenia and neutropenia were more common for H-TPF than L-TPF ( P < 0.001, P < 0.001, P = 0.048). Fewer patients in the H-TPF group finished two cycles of concurrent chemotherapy (81.2% vs. 100%, P < 0.001). Three-year PFS (84.5% vs. 80.6%, P = 0.484) and OS (91.1% vs. 93.5%, P = 0.542) were not significantly different between H-TPF and L-TPF. Conclusions: L-TPF neoadjuvant chemotherapy has substantially better tolerance and compliance rates and similar treatment efficacy to H-TPF neoadjuvant chemotherapy in locoregionally-advanced NPC.

N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epileptic encephalopathies, which pose challenges in clinical treatment. Here we identified a heterozygous GRIN2A mutation (c.1341T>A, p.N447K) from a boy with Rolandic epilepsy by whole-exome sequencing. The patient became seizure-free with a combination of valproate and lamotrigine. Functional investigation was carried out using recombinant NMDARs containing a GluN2A-N447K mutant that is located in the ligand-binding domain of the GluN2A subunit. Whole-cell current recordings in HEK 293T cells revealed that the N447K mutation increased the NMDAR current density by ~1.2-fold, enhanced the glutamate potency by 2-fold, and reduced the sensitivity to Mg(2+) inhibition. These results indicated that N447K is a gain-of-function mutation. Interestingly, alternative substitutions by alanine and glutamic acid at the same residue (N447A and N447E) did not change NMDAR function, suggesting a residual dependence of this mutation in altering NMDAR function. Taken together, this study identified human GluN2A N447K as a novel mutation associated with epilepsy and validated its functional consequences in vitro. Identification of this mutation is also helpful for advancing our understanding of the role of NMDARs in epilepsy and provides new insights for precision therapeutics in epilepsy.

Wheat hybrid necrosis is caused by the interaction of two dominant complementary genes, Ne1 and Ne2, located on chromosome arms 5BL and 2BS, respectively. The sequences of Ne1 or Ne2 have not yet been identified. It is also not known whether Ne1 and Ne2 are structural or regulatory genes. Understanding the proteomic pathways may provide a knowledge base for protecting or maximizing the photosynthesis capacity of wheat. Using DIGE and MALDITOF- TOF MS, the flag leaf protein patterns of the two unique F14 near-isogenic line siblings (NILs), the necrotic ShunMai 12Ah (Ne1Ne1Ne2Ne2) and the normal ShunMai 12Af (Ne1Ne1ne2ne2) were compared. Due to the presence or absence of Ne2, (i) three protein spots were expressed or disappeared, (ii) seven RuBisCO-related proteins were altered significantly, and (iii) 21 photosynthesis/glucose related proteins were changed significantly. Three hypotheses were deduced, (i) Ne1 may also encode protein(s), (ii) genetic maladjustment of RuBisCO could lead to early leaf death, and (iii) interactions between nuclear genes and chloroplast genes could determine photosynthetic traits. Our hypothetical model presents the RuBisCO pathway of hybrid necrosis in wheat and explains how Ne1 and Ne2 interact at molecular level.

Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). Kupffer cells (KCs) are the largest antigen-presenting cell (APC) group and the primary modulators of inflammation in liver tissues. The vital role of Notch1/Jagged1 pathway in mouse OLT model has been reported, however, its potential therapeutic mechanism is unknown. Here, we made use of short hairpin RNA-Jagged1 and AAV-Jagged1 to explore the effects of Notch1/Jagged1 pathway in OLT. In vitro, blockade of Notch1/Jagged1 pathway downregulated the expression of Hairy and enhancer of split-1 (

In this study, autoclaved aerated concrete particles (AACPs) from construction waste were used to simultaneously remove phosphorus and nitrogen in biological aerated filters (BAFs). The effects of ...

Metal-phenolic networks (MPNs) are an emerging class of supramolecular surface modifiers with potential use in various fields including drug delivery. Here, the development of a unique MPN-integrated core-satellite nanosystem (CS-NS) is reported. The "core" component of CS-NS comprises a liposome loaded with EDTA (a metal ion chelator) in the aqueous core and DiR (a near-infrared photothermal transducer) in the bilayer. The "satellite" component comprises mesoporous silica nanoparticles (MSNs) encapsulating doxorubicin and is coated with a Cu2+ -tannic acid MPN. Liposomes and MSNs self-assemble into the CS-NS through adhesion mediated by the MPN. When irradiated with an 808 nm laser, CS-NS liberated the entrapped EDTA, leading to Cu2+ chelation and subsequent disassembly of the core-satellite nanostructure. Photo-conversion from the large assembly to the small constituent particles proceeded within 5 min. Light-triggered CS-NS disassembly enhanced the carrier and cargo penetration and accumulation in tumor spheroids in vitro and in orthotopic murine mammary tumors in vivo. CS-NS is long circulating in the blood and conferred improved survival outcomes to tumor-bearing mice treated with light, compared to controls. These results demonstrate an MPN-integrated multistage nanosystem for improved solid tumor treatment.

Excess bisphenol A (BPA) is a pollutant of concern in different water sources. In this work, magnetic illite clay-composite material (Fe3O4@illite) was synthesized via the coprecipitation method by loading Fe3O4 nanoparticles (nano-Fe3O4) onto the surfaces of illite clay. Results from different characterizations showed that nano-Fe3O4 was embedded into illite clay nanosheets and existed on the surfaces of illite clay, thereby reducing the degree of agglomeration and improving dispersibility. The catalytic BPA degradation of Fe3O4@illite and nano-Fe3O4 confirmed the superior performance of Fe3O4@illite compared with that of nano-Fe3O4. The optimum operating parameters for degradation were 0.3 mL of H2O2 at pH of 3 in the presence of Fe3O4@illite, which provided a maximum degradation capacity up to 816, 364, 113, and 68 mg/g for epoxy BPA concentration of resin wastewater (266 mg/L), synthetic wastewater (80 mg/L), Hefei City swan lake (25 mg/L), and Hefei University lake wastewater (14.94 mg/L), respectively, in 180 min reaction time. The degradation data conformed to the pseudo-first-order kinetic model. The degradation pathways and mineralization study revealed that the adsorption-Fenton-like reaction was the principal mechanism that demonstrated 100% degradation efficiency of Fe3O4@illite even after nine successive runs. The regeneration and reusability tendency analysis ensured that Fe3O4@illite can be easily separated by using magnets. Therefore, Fe3O4@illite composite with H2O2 Fenton-like technology was a promising method for BPA degradation.

Summary Background The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. Methods We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III–IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18–59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m 2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m 2 on day 1), intravenous cisplatin (60 mg/m 2 on day 1), and continuous intravenous fluorouracil (600 mg/m 2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. Findings Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38–49), 3-year failure-free survival was 80% (95% CI 75–85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66–78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48–0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). Interpretation Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. Funding Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Molecular dynamics (MD) simulations of a subtilisin-like serine protease VPR from the psychrophilic marine bacterium Vibrio sp. PA-44 and its mesophilic homologue, proteinase K (PRK), have been performed for 20 ns at four different temperatures (300, 373, 473, and 573 K). The comparative analyses of MD trajectories reveal that at almost all temperatures, VPR exhibits greater structural fluctuations/deviations, more unstable regular secondary structural elements, and higher global flexibility than PRK. Although these two proteases follow similar unfolding pathways at high temperatures, VPR initiates unfolding at a lower temperature and unfolds faster at the same high temperatures than PRK. These observations collectively indicate that VPR is less stable and more heat-labile than PRK. Analyses of the structural/geometrical properties reveal that, when compared to PRK, VPR has larger radius of gyration (Rg), less intramolecular contacts and hydrogen bonds (HBs), more protein-solvent HBs, and smaller burial of nonpolar area and larger exposure of polar area. These suggest that the increased flexibility of VPR would be most likely caused by its reduced intramolecular interactions and more favourable protein-solvent interactions arising from the larger exposure of the polar area, whereas the enhanced stability of PRK could be ascribed to its increased intramolecular interactions arising from the better optimized hydrophobicity. The factors responsible for the significant differences in local flexibility between these two proteases were also analyzed and ascertained. This study provides insights into molecular basis of thermostability of homologous serine proteases adapted to different temperatures.

In this study, autoclaved aerated concrete particles (AACPs) from construction waste were used to simultaneously remove phosphorus and nitrogen in biological aerated filters (BAFs). The effects of air/water (A/W) ratio on the removal performance of phosphorus (PO43−), total organic carbon, total nitrogen (TN), and ammonia nitrogen were investigated. Results showed that AACP BAF was more efficient than commercially available ceramsite (CAC) BAF. For example, the removal rates of TN with AACP and CAC were 45.96% and 15.64%, respectively, and those of PO43− with AACP and CAC were 72.45% and 33.97%, respectively, at the A/W ratio of 3:1. Different characterization methods were utilized to evaluate the surface shape, elemental compostion, and internal and surface structure of AACP. The interconnectivity and uniformity of pores and the rough surface of AACP were found to be suitable for the growth of microbial biofilm. In addition, the growth of internal pores in AACP promoted the removal of phosphorus and nitrogen. The surface of used AACP contained a small amount of irregular crystals and was covered with a layer of aggregates, which were characterized as hydroxyapatite [HAP, Ca5(OH)(PO4)3]. The formation of HAP as a final byproduct confirmed the successful removal of phosphorus. Therefore, construction wastes, such as AACPs, could be recycled and utilized as a promising biofilter media for excellent wastewater treatment.

Phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) has been indicated to serve an important role in the pathogenesis of inflammatory diseases. It was previously demonstrated that the PI3K/Akt inhibitor wortmannin alleviated the severity of inflammation and improved the survival rate in rats with induced severe acute pancreatitis (SAP), which indicates that PI3K/Akt may serve a role in the pathogenesis of acute pancreatitis. To date, the mechanism by which PI3K/Akt regulates inflammation has not been elucidated. In the present study, it was hypothesized that PI3K/Akt may be invovled in SAP inflammation via regulation of the Toll‑like receptor 4 (TLR4) signaling pathway. Rats with SAP were treated with the PI3K/Akt agonist insulin‑like growth factor (IGF)‑1, which alleviated the severity of inflammation in a dose‑dependent manner. Furthermore, to better understand the role of PI3K/Akt in inflammation, RAW264.7 murine macrophages were stimulated with IGF‑1 and wortmannin alone or together before the induction of inflammation by treatment with lipopolysaccharide (LPS). The results indicated that LPS stimulated overexpression of TLR4, myeloid differentiation primary response gene 88 (MyD88), PI3K, Akt, p38MAPK and NF‑κBp65 mRNA, and increased the levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 in RAW264.7 cells compared with the control group. The levels of all detected factors were increased by stimulation with IGF‑1, whereas these levels were decreased following treatment with wortmannin alone, and the effect of IGF‑1 was abolished by wortmannin in RAW264.7 cells. In vivo studies indicated that IGF‑1 produced the same anti‑inflammatory effect as wortmannin and that expression of TLR4, p38MAPK and NF‑κBp65 decreased following treatment with IGF‑1. These findings indicate that PI3K/Akt may take part in the progression of SAP by regulating the TLR4 signaling pathway and that IGF‑1 can inhibit inflammation in SAP rats.